Preparation and use of n-iodopropargyl oxycarbonyl amino acid esters and derivatives as antimicrobial agents

ABSTRACT

Antimicrobial compounds of the formula ##STR1## wherein R 1  is selected from the group consisting of H, lower (C 1  -C 4 )alkyl, alkyl aryl, CH 2  OR, CH 2  SR, and CH(CH 3 )OR; and 
     R, R 2 , and R 3  are independently selected from H, (C 1  -C 4 )alkyl, aryl, arylalkyl, alkaryl, and halopropargyl.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of antimicrobial agents.

2. Description of the Prior Art

Slager, U.S. Pat. No. 3,923,870, discloses iodopropargyl oxycarbamates which are N-substituted with alkyl, aryl, or alkylaryl groups as having fungicidal activity.

Ger. Offen. DE 2515091 (1975), Ciba Geigy AG, discloses microbicidal anilides which are acylanilides which have an amino acid moiety and an iodopropargyl fragment as shown, but the point of attachment of the iodopropargyl fragment is not directly on the amino acid portion of the molecule. These compounds are N-iodopropargyloxy acid amides.

Kokai Tokkyo Koho JP 54/125614 (1979), Shigaken Pharmaceutical Co., Ltd. discloses antimicrobial iodopropargyloxy acid amide derivatives useful for bactericides and agricultural fungicides.

U.S. Pat. No. 4,535,088-A (1985) assigned to Shionogi and Co., shows 2-(3-lodo)propynyl-amino-thiazole derivatives as useful as antimicrobials, i.e. antibacterial and antifungal agents.

Peptides: Synthesis, Structure and Function: Proc. Am. Pept. Symposium, 7th, (1981), pp 101-4 describes the synthesis of C-iodopropargyl glycine. There is no mention of antibacterial or antifungal activity.

SUMMARY OF THE INVENTION

Many of the antimicrobials of the prior art have toxicity and/or environmental problems.

It is an object of the present invention to provide novel antimicrobial compounds which have improved toxicity profiles and are not harmful to the environment.

These objects, and others which will become apparent from the following disclosure, are achieved by the present invention which comprises in one aspect compounds of the formula ##STR2## wherein R¹ is selected from the group consisting of H, lower (C₁ -C₄)alkyl, alkyl aryl, CH₂ OR, CH₂ SR, and CH(CH₃)OR; and

R, R², and R³ are independently selected from H, (C₁ -C₄)alkyl, aryl, arylalkyl, and alkaryl.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The compounds of the invention have been discovered to be unexpectedly effective antimicrobials. The compounds are designed to biodegrade down to non-toxic amino acid components.

Some representative compounds include the following:

    ______________________________________                                         TABLE OF COMPOUNDS (R.sup.3 = H)                                               Compound Number    R.sup.1    R.sup.2                                          ______________________________________                                         1                  H          H                                                2                  H          CH.sub.3                                         3                  H          C.sub.8 H.sub.17                                 4                  H          CH.sub.2 --C.tbd.C--I                            5                  CH.sub.3   H                                                6                  CH.sub.3   CH.sub.3                                         7                  CH.sub.3   C.sub.8 H.sub.17                                 8                  CH.sub.2 Ph                                                                               H                                                9                  CH.sub.2 Ph                                                                               CH.sub.3                                         10                 CH.sub.2 Ph                                                                               C.sub.8 H.sub.17                                 ______________________________________                                    

The compounds of this invention can be prepared by converting the appropriate D- or L-α-amino acid ester hydrochloride to the corresponding 2-isocyanato alkyl ester. The resultant isocyanate compound is reacted with iodopropargyl alcohol to give the N-iodopropargyloxycarbonyl amino acid ester. The free N-iodopropargyloxycarbonyl amino acids are prepared via alkaline hydrolysis of the corresponding ester. Other N-iodopropargyloxycarbonyl amino acid esters are prepared by esterification of the free N-iodopropargyloxycarbonyl amino acid with an appropriate alcohol or alkylhalide utilizing standard known methods.

Iodopropargyl alcohol can be prepared by the procedure described in Bulletin of the Chemical Society of Japan, Ando, T., Shioi, S., Nakagawa, M., (1972) 45, 2611.

The 2-isocyanato alkyl esters are obtained from the corresponding amino acid ester hydrochloride salts by adapting the procedure for preparing 3-isocyanatopropanoyl chloride as described in Organic Synthesis: Collective Volume VI,(1988),715.

As stated above, compositions comprising a compound according to formula I and either an agronomically acceptable carrier, a cosmetic agent, a cutting oil, a soap or synthetic detergent, a stabilizer, a film forming material, or the like have a wide range of utility for protecting against or controlling microorganisms from a wide variety of classes including fungi, bacteria, algae, viruses and yeasts. The preferred utilities of the compositions are to protect wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water from microorganisms.

The following lists specific industries and applications of the compounds or compositions:

    ______________________________________                                         Industry         Application                                                   ______________________________________                                         Adhesives, sealants                                                                             adhesives                                                                      caulks                                                                         sealants                                                      Agriculture/food chain                                                                          adjuvant preservation                                                          agricultural active ingredient                                                 agricultural chemical                                                          preservative                                                                   agricultural formulations                                                      preservation                                                                   animal feed preservation                                                       dairy chemicals                                                                fertilizer preservation                                                        food preservation                                                              food processing chemicals                                                      grain preservation                                                             post-harvest produce protection                                                sugar processing                                                               tobacco                                                       Construction products                                                                           asphalt/concrete                                                               cement modifiers                                                               construction products                                                          roof mastics                                                                   synthetic stucco                                                               wall mastics                                                                   joint cement                                                  Cosmetics and toiletries                                                                        cosmetics                                                                      raw materials for cosmetics,                                                   toiletries                                                                     toiletries                                                    Disinfectants, antiseptics                                                                      antiseptic                                                                     disinfectant                                                  Emulsions, dispersions                                                                          aqueous dispersions                                                            dispersed pigments                                                             latex                                                                          photographic emulsions                                                         pigment slurries                                                               polymer lactices                                              Formulated consumer &                                                                           air fresheners                                                industrial products                                                                             fabric softeners                                                               hand cleaners                                                                  polishes, floor, furniture, shoe                                               sponges & towelettes                                                           spray strach                                                                   waxes                                                         Industrial processing, misc                                                                     dry cleaning fluids preservation                                               electrodeposition paint, baths,                                                rinses.                                                                        electrodeposition pre-treatment,                                               post rinses                                                                    industrial fluids preservation                                                 pasteurization baths                                                           process aid preservation                                      Industrial water treatment                                                                      air washers                                                                    cooling towers                                                                 cooling water                                                                  water cooling                                                 Laundry          household laundry products                                                     laundered goods                                                                laundry rinse water                                                            pre-washers                                                                    sanitizers-laundry                                                             removers, spot & stain                                        Leather, leather products                                                                       leather and hide                                                               leather and hide products                                     Lubricants, hydraulic aids                                                                      automotive lubricants and                                                      fluids                                                                         conveyor lubricants                                                            greases                                                                        hydraulic fluids                                                               hydraulic oils                                                                 lubricants                                                    Medical devices  diagnostic enzymes                                                             diagnostic kits                                                                medical devices                                               Metalworking & related app's                                                                    cutting fluids                                                                 metal cleaning                                                                 metalworking fluids                                           Odor control (active                                                                            air conditioning                                              ingredient)      animal bedding                                                                 cat litter                                                                     chemical toilet prep'ns                                                        deodorizers                                                                    humidifiers                                                                    industrial deodorants                                                          sanitary formulations                                                          toilet bowls                                                  Paints and coatings                                                                             coating emulsions                                                              paints                                                        Paper and wood pulp, their                                                                      absorbant materials of paper and                              products         wood pulp                                                                      packaging materials of paper                                                   and wood pulp                                                                  paper                                                                          paper products                                                                 paper treatment                                                                soap wrap                                                                      wood pulp                                                                      wood pulp products                                            Paper mill       paper mill slimicides                                                          pulp and paper slurries                                       Petroleum refining, fuels                                                                       aviation fuels (jet fuel, aviation                                             gas)                                                                           burner, diesel and turbine fuel                                                oils                                                                           coal slurries                                                                  diesel fuel additives                                                          diesel fuels                                                                   fuels                                                                          gasoline                                                                       heating oils                                                                   hydrocarbons                                                                   kerosene                                                                       liquefied petroleum gas                                                        petrochemical feedstocks                                                       petroleum products storage,                                                    transportation and production                                                  recycled petroleum products                                                    residual fuel oils                                                             turbine oils                                                  Pharmaceutical   topical antifungal and                                                         antibacterial                                                 Photographic chemicals and                                                                      photographic processing - wash                                process          water, rinses                                                                  photoplate processing chemicals                                                (developers, stabilizers etc)                                 Printing         fountain solutions (printing)                                                  ink components (pigments,                                                      rinses, solvents, etc)                                                         inks                                                          Sanitizers (active)                                                                             sanitizers                                                                     sanitizers-dairy                                                               sanitizers-dental                                                              sanitizers-fermentation                                                        sanitizers-food preparation                                                    sanitizers-food processing                                                     sanitizers-medical                                                             sanitizers-rendering                                                           sanitizers-veterinary                                         Soaps, detergents, cleaners                                                                     cleaners                                                                       detergents, hand automatic                                                     laundry, other                                                                 household cleaners                                                             industrial cleaners                                                            liquid soaps, hand, dish,                                                      laundry                                                                        oil and grease remover                                                         powdered soaps                                                                 raw materials for cleaning                                                     products                                                                       soaps                                                                          surfactants                                                   Textiles, textile products                                                                      bonded fabrics                                                                 burlap                                                                         canvas                                                                         canvas goods                                                                   canvas backing                                                                 carpets                                                                        clothing                                                                       coated fabrics                                                                 curtains                                                                       draperies                                                                      engineering textiles                                                           fibers                                                                         geotextiles                                                                    goods made of textiles                                                         knitted fabrics                                                                nets                                                                           nonwoven fabrics                                                               rope                                                                           rugs                                                                           textile accessories                                                            textile products                                                               textiles                                                                       upholstery                                                                     woven fabrics                                                                  yarn                                                          Textile processing                                                                              dye fixatives                                                                  dyes                                                                           fiber lubricants                                                               hand modifiers                                                                 sizes                                                                          textile processing fluids                                     Therapeutic (active or                                                                          animal health/veterinary                                      preservative)    aquaculture                                                                    dental                                                                         human health                                                                   pharmaceutical/therapeutic                                    Water purification                                                                              charcoal beds                                                                  deionization resins                                                            filters                                                                        membranes                                                                      reverse osmosis membranes                                                      ultrafilters                                                                   water purification                                                             water purification pipes, tubing                              Wood applications                                                                               lazures (wood stains)                                                          wood                                                                           wood products                                                 Miscellaneous    alcohols                                                                       bedding incorporating water or                                                 gels                                                                           ceramic                                                                        contact lens cases-leaching                                                    electronic circuitry                                                           electronics chemicals                                                          enzymes-food production                                                        enzymes-industrial                                                             gel cushions                                                                   laboratory reagents                                                            marine antifoulants                                                            mildewcides                                                                    mining applications                                                            natural rubber latex                                                           oil field applications                                                         pipes                                                                          plastics                                                                       polymer systems                                                                polymers and resins (synthetic                                                 and natural)                                                                   reagent preservation                                                           rubber                                                                         rubber products                                                                skin remover                                                                   solid protective/decorative                                                    films                                                                          swimming pools                                                                 waste treatment                                                                water beds                                                    ______________________________________                                    

The amounts of the compound to be used depend on the application. The useful amounts for a particular application are similar to amounts used for other microbicide compounds.

The compound can be used in combination with other microbicides. The term "microbicide" is considered equivalent to "antimicrobial" as used herein.

Suitable methods of application of compounds of formula I to control fungi, bacteria, algae, viruses, yeasts, and the like are in amounts and with carriers, etc., as well known in the art.

The following examples are presented to illustrate a few embodiments of the invention, but are not to be considered as limiting.

EXAMPLE 1 Preparation of N-Iodopropargyloxycarbonyl glycine methyl ester ##STR3##

Trichloromethylchloroformate (18.00 ml., 149.2 mmole) was added to a slurry of glycine methyl ester hydrochloride (12.56 g., 100.0 mmole) in anhydrous 1,4-dioxane (200 ml) and refluxed for 5 hours and then stirred at room temperature for 16 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was distilled to afford the desired intermediate 2-isocyanatoacetic acid methyl ester (10.02 g., 87.1% yield) as a clear colorless liquid. B.P. 67°-68° C. (15-20 mm Hg.); ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =3.84, s, 3H (--OCH₃), 3.97, s, 2H (--N--CH₂ --C).

The 2-isocyanatoacetic acid methyl ester (10.02 g. 87.06 mmole) was dissolved in anhydrous toluene (100 ml) and treated with an anhydrous toluene (50 ml) solution of iodopropargyl alcohol (15.84 g., 87.05 mmole), followed by 6 drops of di-n-butyl tin dilaurate. The reaction mixture was heated at 85° C. for 17.5 hours. After cooling to room temperature, the heterogeneous reaction mixture was diluted with ethyl acetate. The solution was washed with 3×60 ml. of water, 3×60 ml. of 10% aqueous potassium hydrogen sulfate, 3×60 ml. of saturated aqueous sodium bicarbonate, 60 ml. of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 25.50 g. (94.7% crude yield) as a yellow crystalline solid. Recrystallization from methylene chloride/hexane gave 12.97 g. of N-iodopropargyloxycarbonyl glycine methyl ester (Compound 2) as a white crystalline solid (m.p. 93.5°-95.0° C.). ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =3.78, s, 3H (--OCH3), 4.01, d, 2H (--CH₂ --NH--), 4.86, s, 2H (--CH₂ --), 5.33, broad s, 1H, (NH). The mother liquor of compound 2 was concentrated under reduced pressure and the residue chromatographed on 200 g. of silica gel and eluted with a 6:1 mixture of 25% methylene chloride in hexane and ethyl acetate to afford 8.43 g. of N-iodopropargyloxycarbonyl glycine methyl ester (compound 2) as a white crystalline solid. This second crop of material had a m.p. 88°-92° C. The combined total yield for this reaction was 82.8%.

EXAMPLE 2 Preparation of N-Iodopropargyloxycarbonyl Glycine ##STR4##

N-Iodopropargyloxycarbonyl glycine methyl ester (Compound 2, 8.03 g., 27.03 mmole) was dissolved in 100 ml. of tetrahydrofuran, cooled to 0° C. with an ice bath and treated during 15 minutes with 30.5 ml. of 1M aqueous lithium hydroxide. The reaction mixture was stirred at 0° C. for 3/4 hr. or until the starting material was no longer present. The reaction progress was monitored by thin layer chromatography (silica gel, methylene chloride/acetic acid 90:10). After the reaction was complete, the aqueous solution was acidified (pH=2) with 10% aqueous potassium hydrogen sulfate (100 ml) and 3N aqueous hydrogen chloride (10 ml.). This mixture was extracted several times with diethyl ether. The ether layers were combined and washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl glycine (Compound 1) as a pale amber oil, which crystallized upon standing (6.63 g., 86.7% yield after drying in vacuo over P₂ O₅). m.p. 108° -110° C. ¹ H-NMR (200 MHz., DMSOd₆) δ_(ppm) =3.67., d, 2H (--NH--CH₂ --), 4.76, s, 2H (C--CH₂ --O), 7.66, t, 1H (NH).

EXAMPLE 3 Preparation of N-Iodopropargyloxycarbonyl Glycine n-Octyl Ester ##STR5##

N-Iodopropargyloxycarbonyl glycine (compound 1, 6.50 g., 22.97 mmole) was dissolved in anhydrous acetonitrile (100 ml.), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (3.5 ml., 23.40 mmole) and stirred at room temperature for 5 minutes. n-Octylbromide (4.00 ml., 23.16 mmole) was added and the reaction mixture was stirred at room temperature for 17 hours, then heated at reflux temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium chloride, filtered and concentrated under reduced pressure. The resultant residue was purified utilizing column chromatography (silica gel, 200 g.) and eluted with ethyl acetate/hexane (1:10) to afford N-Iodopropargyloxycarbonyl glycine n-octyl ester (Compound 3) as a clear colorless liquid which crystallized on standing. m.p. 43°-46° C. Elemental Analysis: C₁₄ H₂₂ NO₄ l: Calc'd. C: 42.55, H: 5.61, N: 3.54. Found: C: 43.73, H: 5.62, N: 3.54. (Ethyl acetate was present in 0.5 mole %). 1H-NMR (200 MHz, CDCl₃) δ_(ppm) =0.89, m, 3H (--CH₃), 1.30, m, 10H (--(CH₂)₅ --CH₃), 1.64, m, 2H (--CH₂ --), 4.0,d, J=3.4 Hz., 2H (--N--CH₂ --), 4.1-4.2, m, 2H (--CH₂ --), 4.86, s, 2H (C--CH₂ --O), 5.32, m, 1H (--NH--). IR (neat) 3460, 2920, 2850, 2200, 1740, 1560, 1480, 1400, 1360, 1200, 1060, 980 cm⁻¹.

EXAMPLE 4 Preparation of N-lodopropargyloxycarbonyl Glycine Iodopropargyl Ester ##STR6##

N-Iodopropargyloxycarbonyl glycine (compound 1, 4.96 g., 17.52 mmole) was dissolved in a mixture of methylene chloride and 1,4-dioxane (450 ml., 20 ml. respectively) and cooled to 0° C. with an ice bath. Iodopropargyl alcohol (3.51 g., 19.29 mmole) was added, followed by 4-dimethylaminopyridine (0.22 g., 1.80 mmole) and N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.17 g., 21.75 mmole). The reaction mixture was stirred at 4° C. for 17 hours. Upon warming to room temperature, the reaction mixture was diluted with methylene chloride, washed with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl glycine iodopropargyl ester (compound 4) as a white crystalline solid (8.26 g.). m.p. 86°-88° C.; ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =4.05, d, J=5.6 Hz., 2H (NH--CH₂ --), 4.89, d, J=10.2 Hz., 4H (C--CH₂ --O), 5.32, m, 1H (--NH--).

EXAMPLE 5 Preparation of N-Iodopropargyloxycarbonyl Alanine Methyl Ester ##STR7##

L-Alanine methyl ester hydrochloride (6.00 g., 42.99 mmole) was slurried in anhydrous 1,4-dioxane (125 ml.), treated with trichloromethylchloroformate (7.8 ml., 64.66 mmole) and heated at 55° C. for 20.5 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was subjected to distillation to afford the desired intermediate 2-isocyanatopropionic acid methyl ester (4.64 g., 83.6% yield) as a clear colorless liquid. B.P. 58° C. (15-20 mm Hg.). ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =1.54, d, J=8 Hz., 3H (--CH₃), 3.87, s, 3H (--OCH₃), 4.13, q, J=8 Hz., 1H(--CH--CH₃), IR(neat) 3000, 2960, 2270, 1745, 1455, 1445, 1385, 1305, 1230, 1110 cm⁻¹.

An anhydrous toluene solution (30 ml.) of iodopropargyl alcohol (6.60 g., 36.27 mmole) was added to an anhydrous solution (40 ml.) of 2-isocyanatopropionic acid methyl ester (4.64 g., 35.94 mmole) and the reaction mixture was stirred at room temperature for 2.5 hours, then at 70° C. for 17 hours. When cool, the reaction mixture was diluted with toluene and washed with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to form a yellow crystalline solid (9.55 g., 85.4% crude yield). The crude material was recrystallized from ethyl acetate/hexane to afford N-iodopropargyloxycarbonyl alanine methyl ester (compound 6, 5.85 g.) as a white crystalline solid. m.p. 100°-102° C. ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =1.43, d, J=8 Hz., 3H(--CH₃), 3.77, s, 3H (--OCH₃), 4.38, m, 1H (--CH--CH₃), 4.85, d, J=2.7 Hz., 2H (--C--CH₂ --O), 5.39, m, 1H (--NH--). IR (CHCl3) 3450, 2970, 2210, 1735, 1515, 1469, 1350, 1080 cm⁻¹.

EXAMPLE 6 Preparation of N-Iodopropargyloxycarbonyl Alanine ##STR8##

N-iodopropargyloxycarbonyl alanine methyl ester (compound 6, 4.00 g., 12.86 mmole) was dissolved in a tetrahydofuran/water mixture (3:1, 100 ml.) and cooled to 0° C. with an ice bath. Lithium hydroxide (0.35 g., 14.61 mmole) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, redissolved in water and acidified with 10% aqueous potassium hydrogen sulfate. The aqueous mixture was extracted with methylene chloride several times. The combined methylene chloride layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl alanine (compound 5, 2.72 g., 71.2% yield) as a white crystalline solid. m.p. 95°-99° C.; ¹ H-NMR (200 MHz, DMSOd₆) δ_(ppm) =1.28, d, J=8 Hz., 3H (--CH--CH₃), 4.00, m, 1H (--CH--CH₃), 4.75, s, 2H (--CH₂ --O), 7.7, d, J=8 Hz., 1H (--NH--), 12.57, s, 1H (--COOH). IR (KBr) 3500-2000, 2200, 1670-1715, 1530, 1450, 1335, 1250, 1075, 1050 cm⁻¹.

EXAMPLE 7 Preparation of N-Iodopropargyloxycarbonyl Alanine ##STR9##

N-iodopropargyloxycarbonyl alanine (compound 5, 0.95 g., 3.20 mmole) was dissolved in anhydrous N,N-dimethylformamide (15 ml.) and treated with the following: n-octanol (0.60 ml., 3.81 mmole), N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.68 g., 4.07 mmole) and 4-dimethylaminopyridine (0.041 g., 0.336 mmole). The reaction mixture was stirred at room temperature for 10 minutes, then held at 4° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium carbonate, water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an oil. The oil was chromatographed on silica gel (50 g.) and eluted with hexanes/ethyl acetate (9:1) to afford N-iodopropargyloxycarbonyl alanine n-octyl ester (compound 7, 0.97 g., 74% yield) as a clear colorless oil. ¹ H-NMR (200 MHz., CDCl₃) δ_(ppm) =0.93, m, 3H (--CH₂ --CH₃), 1.34, m, 10H (--(CH₂)₅ --CH₃), 1.47, d, J=8 HZ., 3H (--CH--CH₃), 1.7, m, 2H (--CH₂ --), 4.18, t, J=8 Hz., 2H (--O--CH₂ --CH₂ --), 4.4, m, 1H (--CH--CH₃), 4.87, s, 2H (--C--CH₂ --O), 5.42, m, 1H (--NH--). IR (CHCl₃) 3440, 2940, 2870, 2210, 1745, 1505, 1455, 1340, 1070 cm⁻¹. IR (neat) 3350, 2930, 2860, 2200, 1740, 1515, 1445, 1070 cm⁻¹.

EXAMPLE 8 Preparation of N-Iodopropargyloxycarbonyl Phenylalanine Methyl Ester ##STR10##

L-Phenylalanine methyl ester hydrochloride (6.00 g., 27.82 mmole) was slurried in anhydrous 1,4-dioxane (125 ml.), treated with trichloromethylchloroformate (5.05 ml., 41.86 mmole) and heated at 55° C. for 17.5 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was subjected to high vacuum distillation to afford the desired intermediate 2-isocyanato-3-phenylpropionic acid methyl ester (4.78 g., 84% yield). B.P. 83°-85° C. (100 μm Hg.) as a clear colorless liquid. ¹ H-NMR (200 MHz, CDCl₃) δ_(ppm) =3.12, dd, J=8.5 Hz., 2H (--CH₂ --Ph), 3.83, s, 3H (--COOCH₃), 4.28, m, 1H (--CH--CH₂ --), 7.15-7.4, m, 5H (Ar--H).

An anhydrous toluene solution (50 ml.) of iodopropargyl alcohol (4.66 g., 25.61 mmole) was added to an anhydrous toluene solution (50 ml.) of 2-isocyanato-3-phenylpropionic acid methyl ester (4.78 g., 23.29 mmol) containing 5 drops of di-n-butyl tin dilaurate and the reaction mixture was stirred at room temperature for 17 hours. When cool, the reaction mixture was diluted with toluene and washed with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to form N-iodopropargyloxycarbonyl phenylalanine methyl ester (compound 9) as a white crystalline solid (8.87 g., 98.3% yield). m.p. 100°-103° C.; ¹ H-NMR (200 MHz, CDCL₃) δ_(ppm) =3.13, m, 2H (--CH₂ --Ph), 3.75, s, 3H (COOCH₃), 4.65, m, 1H (--CH--), 4.83, s, 2H (C--CH₂ --O), 5.25 , m, 1H (--NH--), 7.05-7.4, m, 5H (Ar--H).

EXAMPLE 9 Preparation of N-Iodopropargyloxycarbonyl Phenylalanine ##STR11##

N-iodopropargyloxycarbonyl phenylalanine methyl ester (compound 9, 7.05 g., 18.21 mmole) was dissolved in a tetrahydofuran/water mixture (3:1, 100 ml.) and cooled to 0° C. with an ice bath. Lithium hydroxide (0.483 g., 20.17 mmole) was added and the reaction mixture was stirred for 1.5 hours. An additional amount of lithium hydroxide (45 mg.) was added to the reaction mixture and stirring was continued for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove the tetrahydrofuran, redissolved in water and acidified with 10% aqueous potassium hydrogen sulfate. The resultant white precipitate was isolated by filtration. The solid waS dissolved in diethyl ether and washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford N-iodopropargyloxycarbonyl phenylalanine (compound 8, 5.97 g., 87.8% yield) as a white crystalline solid. ¹ H-NMR (200 MHz., DMSOd₆) δ_(ppm) =2.95, dd, J=4, 16 Hz., 2H (--CH₂ --Ph), 4.15, m, 1H (--CH--CH₂ --), 4.7, s, 2H (--C--CH₂ --O), 7.3, m, 5H (Ar--H), 7.75,d, J=8 Hz., 1H (--NH--), 12.8, m, 1H (COOH). IR (CHCl₃) 3600-2400, 3420, 2200, 1730, 1500, 1065 cm⁻¹.

EXAMPLE 10 Preparation of N-Iodopropargyloxycarbonyl Phenylalanine ##STR12##

N-iodopropargyloxycarbonyl phenylalanine (compound 8, 2.00 g., 5.36 mmole) was dissolved in anhydrous 1,4-dioxane (20 ml.) and treated with the following: n-octanol (0.95 ml., 6.03 mmole), N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.08 g., 6.47 mmole) and 4-dimethylaminopyridine (0.073 g., 0.598 mmole). N,N-Dimethylformamide (5.00 ml.) was added to the heterogeneous reaction mixture to effect a homogeneous solution. The reaction mixture was stirred at room temperature for 10 minutes, then held at 4° C. for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the 1,4-dioxane, diluted with methylene chloride and washed with water, 10% aqueous potassium hydrogen sulfate, water, saturated aqueous sodium carbonate, water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a viscous pale yellow oil which solidified on standing. The oil was chromatographed on silica gel (70 g.) and eluted with hexanes/ethyl acetate (9:1) to afford N-iodopropargyloxycarbonyl phenylalanine n-octyl ester (compound 10, 1.98 g., 76.2% yield) as a white crystalline solid. ¹ H-NMR (200 MHz., CDCl₃) δ_(ppm) =0.9, m, 3H (--CH₃), 1.3, m, 10H (--(CH₂)₅ --CH₃), 1.58, m, 2H (--CH₂ --), 3.13,d, J=5 Hz., 2H (--CH₂ --Ph), 4.1, t, J=5 Hz., 2H (--O--CH₂ --CH₂ --), 4.63, m, 1H (--CH--CH₂ --), 4.72, s, 2H (C--CH₂ --O), 5.27, d, J=8 Hz., 1H (--NH--), 7.1-7.35, m, 5H (Ar--H). IR (CHCl3) 3440, 2940, 2870, 1730, 1505, 1355, 1120 cm⁻¹.

EXAMPLE 11--BIOLOGICAL ACTIVITY A. Biocidal Activity:

Biocidal evaluations (bactericidal, algicidal, and fungicidal) were carried out.

A minimum inhibitory concentration (MIC) value is obtained using a broth, two-fold serial dilution test performed as follows: A stock solution or dispersion of the test compound, typically at a concentration of 1%, is made in a 5:3:2 solvent solution of acetone, methanol, and water. A volume of the stock solution is dispensed into culture media to give an initial starting test concentration of 500 ppm compound.

When the test is ready to be done, each vessel in the dilution series, except the first vessel, contains an equal volume of compound free broth. The first vessel contains twice the volume of broth with the starting concentration of test compound. One half of the broth from the first vessel is transferred to the second vessel. After being mixed, one half the resulting volume is removed from the second vessel and transferred to the third vessel. The entire cycle is repeated sufficiently to give a series of concentrations amounting to 500, 250, 125, 63, 31, 16, 8, and 4 ppm (or 100, 50, 25, 12.5, 6.2, 3.1, 1.6, and 0.8), respectively.

Each vessel is then inoculated with a cell suspension of the appropriate test organism. Bacteria are grown in broth, fungi on agar slants for a time and at a temperature appropriate to the species being tested, and algae are a mixture of green algae and blue-green bacteria grown in a nutrient media. At the end of the growth period, in the case of bacteria, the broth is vortexed to disperse the cells.

In the case of fungi, the spores are harvested by pipetting water onto the slant and dislodging the spores with a sterile loop. The cell/spore suspension is standardized by controlling incubation time, temperature, and the volume of the diluent. The suspension is then used to inoculate the vessels containing the broth compound.

The algae culture contains green algae and blue-green bacteria, and is obtained from a cooling tower in Spring House, Penn. The algae culture is grown in Allen's medium on a rotary shaker under flourescent room lighting. This culture is further diluted with Allen's medium and then added to the test vessel.

The vessels are then incubated at the appropriate temperature. After the incubation, the vessels are examined for growth/no growth. The minimum inhibitory concentration (MIC) is defined as the lowest concentration of compound that results in complete inhibition of growth of the test organism.

The organisms tested to demonstrate biocidal activity include:

BACTERIA:

Pseudomonas fluorescens (PSFL), gram negative

Pseudomonas aerugenosa (PSAE), gram negative

Escherichia coli (ECOL), gram negative

Staphylococcus aureus (SAUR), gram positive

FUNGI:

Aspergillus niger (ANIG)

Aureobasidium pullulans (APUL)

The results of the minimum inhibitory concentration (MIC) tests of compounds of this invention are shown in Table I against the microorganisms shown in Table II.

                                      TABLE 1                                      __________________________________________________________________________     BIOCIDES SECONDARY MIC TEST DATA IN PPM                                        These compounds were tested in M9G                                             (minimal salts media with glucose)                                             Compound                                                                             (G-)                                                                               (G-)                                                                               (G-) (G+)                                                                               (F)  (F)                                                #     PSFL                                                                               PSAE                                                                               ECOL SAUR                                                                               ANIG APUL ALGAE                                         __________________________________________________________________________     1     250 >500                                                                               250  250 >500 >500                                               2     16    32                                                                                32  16  <4   <4                                                 3      8  >500                                                                               >500  8  <4   <4                                                 4     32   125                                                                               125  32    <0.12                                                                               <0.12                                                                             12.5                                          5     125 >500                                                                               125  250 125   32                                                6     <4    32                                                                               <4   16  <4   <4                                                 7      8   125                                                                               <4   63  <4   <63                                                8     63   250                                                                               <4   125 250  250                                                9     125 >500                                                                               >500 125 <4   <4                                                 10    32    63                                                                               <4   32  125  125                                                __________________________________________________________________________

                  TABLE II                                                         ______________________________________                                         MICROORGANISMS USED IN THE BIOCIDES TESTS                                                        GRAM       Abbreviation                                      NAME              ATCC No.   used                                              ______________________________________                                         BACTERIA                                                                       1. Pseudomonas aeruginosa (-)                                                                    15442      PSAE                                              2. Staphylococcus aureus (+)                                                                     6538       SAUR                                              3. Escherichia coli (-)                                                                          11229      ECOL                                              4. Pseudomonas fluorescens (-)                                                                    948       PSFL                                              FUNGI                                                                          5. Aspergillus niger                                                                             6275       ANIG                                              6. Aureobasidium pullulans                                                                       9348       APUL                                              ______________________________________                                     

We claim:
 1. Compounds of the formula ##STR13## wherein R¹ is selected from the group consisting of H, lower (C₁ -C₄)alkyl, alkyl aryl, CH₂ OR, CH₂ SR, and CH(CH₃)OR; andR, R², and R³ are independently selected from H, (C₁ -C₄)alkyl, aryl, arylalkyl, alkaryl, and halopropargyl.
 2. Compound according to claim 1 wherein said compound is selected from the group consisting of N-iodopropargyloxycarbonyl glycine methyl ester; N-iodopropargyloxycarbonyl glycine; N-iodopropargyloxycarbonyl glycine n-octyl ester; N-iodopropargyloxycarbonyl glycine iodopropargyl ester; N-iodopropargyloxycarbonyl alanine methyl ester; N-iodopropargyloxycarbonyl alanine; N-iodopropargyloxycarbonyl alanine n-octyl ester; N-iodopropargyloxycarbonyl phenylalanine methyl ester; N-iodopropargyloxycarbonyl pheylalanine; N-iodopropargyloxycarbonyl phenylalanine; and n-octyl ester.
 3. Process for preventing or controlling the growth of microorganisms in a locus comprising introducing or applying a microbicidally effective amount of a compound according to claim 1 as an antimicrobial agent at, into, or onto said locus.
 4. Process according to claim 1 wherein said microorganism is bacteria, fungi, and/or algae.
 5. Process comprising using a compound according to claim 1 to control industrial fungi.
 6. Process comprising using a compound according to claim 1 to control bacteria.
 7. Process according to claim 1 wherein said microorganism is algae, viruses or yeasts.
 8. Process according to claim 1 wherein said locus is a material selected from the group consisting of wood, paint, adhesive, glue, paper, textile, leather, plastics, cardboard, lubricants, cosmetics, food, caulking, feed and industrial cooling water.
 9. Process according to claim 1 wherein said compound is used as a topical antifungal and/or antibacterial agent on human skin. 